Keir Neuman graduated cum laude with a B.A. in physics and applied math from the University of California, Berkeley in 1994 and received his Ph.D. in physics from Princeton University in 2002. He did postdoctoral research with Steven Block at Stanford University from 2002 to 2004, and was a Human Frontiers Fellow with David Bensimon and Vincent Croquette at the Laboratoire de Physique Statistique at the École Normale Supérieure in Paris, France from 2004 to 2007. Dr. Neuman joined the NHLBI as a tenure-track Investigator in 2007. In 2010, he was awarded a Human Frontiers Young Investigator Grant with Mihály Kovács from the Department of Biochemistry at Eötvös University in Hungary. Dr. Neuman is a reviewer for numerous journals and grant organizations. He is also a member of the Biophysical Society, the Optical Society of America, and the American Physical Society.
Enzymes are typically studied in ensembles. Enzyme mechanism has traditionally been elucidated from biochemical and structural experiments that involve thousands or millions of molecules. Enzymes, however, are complex molecular machines that, when subjected to individual scrutiny, reveal features that cannot be ascertained from ensemble approaches. Single-molecule visualization and manipulation techniques are at the technological forefront of biological enquiry; these techniques can probe distances on the sub-nanometer (10-9 M) scale and forces on the piconewton (10-12 N) scale with millisecond temporal resolution. Dr. Neuman employs these techniques—including optical and magnetic tweezers and fluorescence imaging, in combination with conventional molecular biology approaches—to answer fundamental questions concerning enzyme function and regulation. His research program is underpinned by single-molecule instrumentation that his laboratory designs and builds to elucidate enzyme mechanisms at the molecular level.
Approximately two meters of DNA is compacted into a cell’s nucleus, which leads to topological complications during replication, transcription, and segregation of chromosomes. Topoisomerases are essential enzymes that regulate DNA topology and are important chemotherapeutic and antibiotic drug targets; Dr. Neuman focuses on elucidating the molecular mechanisms of topoisomerase activity and inhibition by chemotherapeutic agents. Employing magnetic tweezers, Dr. Neuman’s laboratory is answering two outstanding mechanistic questions: how some type II topoisomerases can discriminate the handedness of supercoiled DNA and how all type II topoisomerases are able to relax DNA topology below equilibrium. In parallel with this research on type II topoisomerases, Dr. Neuman is investigating the catalytic activity of human nuclear type IB topoisomerase and its unique sensitivity to anti-cancer reagents.
Topoisomerases interact with many other enzymes that regulate DNA. Dr. Neuman is extending the use of single-molecule techniques to dissect multi-enzyme complex formation and activity. For this work, he focuses on the combination of RecQ helicase and topoisomerase III, which is a conserved interaction in organisms ranging from E. coli through humans and plays important roles in genome stability and chromosome segregation.
More recently, Dr. Neuman has turned his attention away from the cell nucleus to study the interaction between the structural protein collagen and the matrix metalloproteinase enzymes that degrade it (collagenases). Collagen exists in long fibers that are virtually impossible to study biochemically, due primarily to their insolubility and heterogeneity. Dr. Neuman is studying the motion of collagenase enzymes as they move along and degrade individual intact native collagen fibers extracted from rat tails. He has discovered several novel aspects of the collagen fiber itself, such as high-affinity binding sites that are periodically spaced at intervals far longer than the monomer, implying a secondary level of organization. He has also found an unsuspected level of complexity in the cleavage process, which involves a sequence of ~10 kinetic steps for cleavage initiation, followed by 15 rounds of very rapid unidirectional cleavage. The slow initiation process suggests an entirely new form of regulation of this enzymatic degradation reaction, which is important in a host of human pathological and physiological process such as the rupture of atherosclerotic plaques and cancer metastasis.